Pain relief implant pellet and method using same

ABSTRACT

An emplantable pellet comprising one or more pain relief agents. A method to relief pain at the injection site of one or more implanted pharmaceutical pellets comprising the step of implanting one or more of Applicant&#39;s implantable pellets. A method to adjust the in vivo rate of release of one or more pain relief agents from Applicants&#39; implantable pellets. A method to adjust the rate of systemic delivery of one or more pharmaceutical agents implanted adjacent one or more of Applicants&#39; implantable pellets.

FIELD OF THE INVENTION

The present invention is broadly concerned with a pain reliefcomposition in implantable pellet form, and a method to relieve painusing such implantable pellets.

BACKGROUND OF THE INVENTION

Animal well-being and treatment are major concerns for animal welfaregroups and animal agriculturalists. Animal well-being and treatment arecontinual concerns because stressed or uncomfortable animals do notefficiently and profitably produce milk, meat, or eggs.

Implant technology, that is to say, procedures involving subcutaneousimplant of pharmaceuticals and medical devices, is now well accepted andwidespread in the areas of animal health and production enhancement aswell as human health. Growth stimulants are commonly used to enhance thebody weight of animals which are raised for harvesting, such as cattle,swine, sheep, turkeys, chickens, and the like.

In the case of cattle and sheep, approved growth stimulants areadministered as solid pellets which are injected by an implanterequipped with a hypodermic needle. The needle is used to make a surfaceself-sealing and, non-coring implant receiving puncture beneath the skinof the ear of the animal. Small pellets of growth-promoting hormones areforced through the needle and left under the skin as the needle isremoved from the ear. The ears are commonly discarded in harvesting,such that no unabsorbed residues of such pellets will end up in foodproducts intended for humans or domestic animals. The pharmaceutical inthe pellets is normally formulated for timed release and continuous,sustained absorption of the active ingredients over an extended periodof time.

Many types of pharmaceuticals such as bioactive compounds may also beimplanted and include insulin, endocrine hormones for control ofreproduction, vaccines, and biocides for flea and parasite control inhumans, horses, and domestic animals such as dogs and cats. Thecompounds may be administered subcutaneously at any suitable location onthe body. Included as such a pharmaceutical are synthetic derivatives ofnaturally occurring compounds such as trenbolone acetate, a syntheticderivative of testosterone currently used in cattle growth-promotingimplants. As those skilled in the art will appreciate, similartherapeutic procedures may be employed to implant drug delivery devicessuch as controlled release osmotic pumps in humans and animals as wellas transponder devices in animals.

In the case of food-producing animals, the pellets are normallyimplanted while an animal is confined in a chute. An ear is grasped inone hand, and an implanter device having a large hypodermic needle isused to puncture the hide and subcutaneously inject a pellet dose intoan implant-receiving puncture. The implanting must be done carefully toinsure that the pellets are properly placed and that no pellet remainsextending from the puncture outside the hide. The procedure must becarried out quickly since the animals are not entirely cooperative andmay shake their heads to free the held ear.

In addition to implanting pharmaceutical pellets, is it also known inthe art to implant certain anti-inflammatory agents. As those skilled inthe art will appreciate, when tissue injury occurs, whether caused bybacteria, trauma, chemicals, heat, or any other phenomenon, the body'sinflammatory response is stimulated. In response to signals releasedfrom the damaged cells (e.g., cytokines), extravascularization of immuneeffector cells is induced. Under ordinary circumstances these invadingimmune effector cells kill the infectious agent and/or infected ordamaged cells (through the release of killing substances such assuperoxides, performs, and other antimicrobial agents stored ingranules), remove the dead tissues and organisms (through phagocytosis),release various biological response modifiers that promote rapid healingand covering of the wound (quite often resulting in the formation offibrotic scar tissue), and then, after the area is successfully healed,exit from the site of the initial insult.

Once the site is perceived to be normal, the local release ofinflammatory cytokines ceases and the display of adhesion molecules onthe vessel endothelium returns to basal levels. In some cases, however,the zeal of these interacting signals and cellular systems, which aredesigned to capture and contain very rapidly multiplying infectiousagents, act to the detriment of the body, killing additional, otherwisehealthy, surrounding tissue. This additional unnecessary tissue deathfurther compromises organ function and sometimes results in death of theindividual.

The present invention provides a pain relief pellet system whichdelivers localized, controlled and sustained release of a predeterminedquantity of one or more pain relief agents, in optional combination withone or more anti-inflammatory agents, one or more polymeric excipients,and/or one or more surfactants. Applicants' anesthetic/analgesic pelletsystem can be used in combination with one or more pharmaceuticalimplants as part of a single procedure in order to provide desiredpharmaceutical to the animal while simultaneously alleviating pain and,optionally, inflammation at the injection site.

SUMMARY OF THE INVENTION

The present invention includes an implantable pain relief pellet.Applicants' invention further includes a method for implantation ofsame. In certain embodiments, Applicants' method also includesimplantation of one or more pharmaceutical pellet, thereby providinglocalized, sustained, anesthetic/analgesic release at an injection sitein order to reduce pain around the site of the injection.

In certain embodiments, Applicants' method also includes implantation ofone or more anti-inflammatory pellets, thereby providing localized,sustained, anti-inflammatory release at an injection site in order toreduce inflammation around the site of the injection.

Applicants' invention further comprises a pellet system which includesan implanter apparatus for subcutaneously injecting pharmaceuticalpellets into an animal through the bore of a hypodermic needle which isremotely coupled to a pellet magazine, and simultaneously implanting oneor more anesthetic/analgesic/anti-inflammatory pellet into the injectionsite. Applicants' invention further includes a method comprisingimplantation of predetermined doses of one or more pharmaceutical orcombination and an anesthetic/analgesic/anti-inflammatory agent(s) in asingle injection.

Applicants' invention further comprises a method which permits anoperator to selectively implant an anesthetic/analgesic dose into ananimal, including humans. Applicants' invention further comprises amethod which permits serial injection of large numbers of animals in asingle session.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be better understood from a reading of the followingdetailed description taken in conjunction with the drawings in whichlike reference designators are used to designate like elements, and inwhich:

FIG. 1 is a fragmentary perspective view of an implantation apparatus ofuse when employing Applicants' method to relieve pain;

FIG. 2 is a fragmentary cross-sectional view showing Applicants'implantable pain relief pellets disposed within the implantationapparatus;

FIG. 3 is a fragmentary cross-sectional view showing implantation ofApplicants' pain relief pellets;

FIG. 4 recites Applicants' formulations A through S, wherein thoseformulations comprise one or more anesthetic agents in combination withone or more analgesic agents;

FIG. 5A recites Applicants' formulations AA through AS which include oneor more anesthetic agents in combination with one or more additionalingredients;

FIG. 5B recites Applicants' formulations AT through BL which include oneor more anesthetic agents in combination with one or more additionalingredients;

FIG. 6A recites Applicants' formulations CA through CS which include oneor more analgesic agents in combination with one or more additionalingredients;

FIG. 6B recites Applicants' formulations CT through DL which include oneor more analgesic agents in combination with one or more additionalingredients;

FIG. 7A recites Applicants' formulations EA through ES which include oneor more anesthetic agents in combination with one or more analgesicagents in combination with one or more additional ingredients; and

FIG. 7B recites Applicants' formulations ET through FL which include oneor more anesthetic agents in combination with one or more analgesicagents in combination with one or more additional ingredients.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

It is to be understood that the disclosed embodiments are merelyexemplary of the invention, which may be embodied in various forms.Therefore, specific structural, composition, and/or functional detailsdisclosed herein are not to be interpreted as limiting, but merely as abasis for the claims and as a representative basis for teaching oneskilled in the art to variously employ the present invention invirtually any appropriately detailed structure, composition, and/ormethod.

Applicants' invention comprises an implantable pellet comprising one ormore pain relief agents. By pain relief agent, Applicants mean one ormore anesthetic agents and/or one or more analgesic agents. Byanesthetic agent, Applicants mean a composition that induces a partialor total loss of the sense of pain, temperature, touch, and the like. Byanalgesic agent, Applicants mean a composition that induces a state ofnot being able to feel pain. Applicants' pain relief pellet can beformed by various methods including, but not limited to, compressionmolding and/or encapsulation.

In certain embodiments, Applicants' pain relief pellets comprise one ormore anesthetic agents, including those used in caudal, epidural,inhalation, injectable, retrobulbar, and spinal applications, such asbupivacaine, lidocaine, prilocaine, and mixtures thereof. In theseembodiments, the one or more anesthetic agents are present in an amountbetween about 5 weight percent and about 95 weight percent. FIGS. 5A and5B recite Applicants' formulations AA through BL which include one ormore anesthetic agents in combination with one or more additionalingredients discussed below.

In alternative embodiments, Applicants' pain relief pellets comprise oneor more analgesic agents, such as acetaminophen, ibuprofen, fluriprofen,ketoprofen, voltaren, phencetin, salicylamide, and mixtures thereof. Inthese embodiments, the one or more analgesic agents are present in anamount between about 5 weight percent and about 95 weight percent. FIGS.6A and 6B recite Applicants' formulations CA through DL which includeone or more analgesic agents in combination with one or more additionalingredients discussed below.

In yet other embodiments, Applicants' pain relief pellets comprise oneor more anesthetic agents in combination with one or more analgesicagents. In these embodiments, the one or more anesthetic agents incombination with the one or more analgesic agents are present in anaggregate amount between about 5 weight percent and about 95 weightpercent. FIG. 4 recites Applicants' formulations A through S, whereinthose formulations comprise one or more anesthetic agents in combinationwith one or more analgesic agents.

The weight percentages recited in FIG. 4 represent only theanesthetic/analgesic component of Applicants' pain relief formulation.In contrast, each formulation recited in FIGS. 7A and 7B includes one ofthe formulations recited in FIG. 4 in combination with one or moreadditional ingredients discussed below. For example, formulation EA(FIG. 7A) comprises an anesthetic agent(s)/analgesic agent(s) componentpresent at about 95 weight percent in combination with a surfactantcomponent present at about 5 weight percent. The anestheticagent(s)/analgesic agent(s) component of formulation EA includes any ofthe formulations recited in FIG. 4. Thus, formulation EA includes atabout a 95 weight percentage level, one or more of compositions AAthrough AS.

In certain embodiments, Applicants' implantable pellet also comprisesone or more anti-inflammatory agents. By anti-inflammatory agent,Applicants mean a composition that minimizes injury-produced vasculardilatation and the greatly increased blood flow associated therewith,and/or exudation of fluid from blood vessels into tissues withconcomitant swelling, and/or migration of leukocytes into the tissues,and/or gelation of fibrogen in intercellular spaces.

In certain embodiments, the one or more anti-inflammatory agents areselected from the group comprising, but not limited to, corticosteriods,keratolytics, and mixtures thereof. The one or more anti-inflammatoryagent components of Applicants' composition are present in an amount upto about 90 weight percent.

Applicants' composition is formulated so as to be biodegradable in thetarget animals, including humans, and to control release of the activeingredients. In certain embodiments, Applicants' anesthetic compositionincludes one or more excipients, including but not limited to,polyethylene glycol, starch, dextran, polyvinylalcohol, poly2-ethyl-2-oxazoline, and mixtures thereof. In certain embodiments, suchexcipients are present in an amount at up to about 50 weight percent. Inother embodiments, such excipients are present in an amount betweenabout 5 weight percent and about 25 weight percent. In alternativeembodiments, such excipients are present in an amount between about 10weight percent and about 20 weight percent.

Poly-2-ethyl-2-oxazoline is a water-soluble polymeric material. As thoseskilled in the art will appreciate, poly 2-ethyl-2-oxazoline comprisessubstituted polyethyleneimine II. Polymer II can be formed by aring-opening polymerization of 2-ethyloxazoline I.

In certain embodiments, Applicants' implantable composition includespolymer II having a number average molecular weight of about 5,000, i.e.n equals about 50. This polymeric material is sold in commerce under thename AQUAZOL® 5 by Polymer Chemistry Innovations, Inc., 4231 SouthFremont, Tucson, Ariz. 85714. In other embodiments, Applicants'implantable composition includes polymer II having a number averagemolecular weight of about 50,000, i.e. n equals about 500. Thispolymeric material is sold in commerce under the name AQUAZOL® 50 byPolymer Chemistry Innovations, Inc. In alternative embodiments,Applicants' implantable composition includes polymer II having a numberaverage molecular weight of about 500,000, i.e. n equals about 5000.This polymeric material is sold in commerce under the name AQUAZOL® 500by Polymer Chemistry Innovations, Inc.

In certain embodiments, Applicants' pain relief pellets comprise one ormore surfactants. Such surfactants are selected from the groupconsisting of anionic surfactants, amphoteric surfactants, non-ionicsurfactants, and mixtures thereof. Certain embodiments of Applicants'pain relief pellet include one or more nonionic surfactants having aHydrophilic Lipophilic Balance (“HLB”) between about 5 and about 20.Such nonionic surfactants include polyoxyethylene/polyoxypropylene blockco-polymers, polyoxyethylene/alkyl ethers, polyoxyethylene sorbitanesters, and mixtures thereof. In certain embodiments, the surfactantcomponent of Applicants' implantable composition is present in an amountup to about 20 weight percent. In other embodiments, such one or moresurfactants are present in an amount between about 1 weight percent andabout 10 weight percent. In alternative embodiments, such one or moresurfactants are present in an amount between about 3 weight percent andabout 5 weight percent.

The rate of in vivo release from an implanted pellet comprising one ormore anesthetic agents, and/or one or more analgesic agents, and/or oneor more anti-inflammatory agents, can be adjusted by: (i) varying theweight percentage of one or more water soluble polymeric excipients,such as poly 2-ethyl-2-oxazoline, and/or (ii) including a firstsurfactant and varying the weight percentage of that first surfactant,(iii) including a first surfactant at a first weight percentage leveland a second surfactant at a second weight percentage level, and varyingthe ratio between said first weight percentage level and said secondweight percentage level, and/or (iv) including one or more non-ionicsurfactant(s) and varying the HLB(s) of those one or more non-ionicsurfactants. Thus, the inclusion of a water-soluble, polymeric excipientin combination with one or more surfactant allows the formulator toadjust the rate of time release of the anaesthetic agents/analgesicagents/anti-inflammatory agents comprising Applicants' implantablepellets. In addition, the rate of systemic delivery of one or morepharmaceutical agents released from a pharmaceutical pellet implanted inan animal and disposed adjacent one or more of Applicants' implantablepellets can be adjusted by: (i) including a first surfactant and varyingthe weight percentage of that first surfactant, (ii) including a firstsurfactant at a first weight percentage level and a second surfactant ata second weight percentage level, and varying the ratio between saidfirst weight percentage level and said second weight percentage level,and/or (iii) including one or more non-ionic surfactant(s) and varyingthe HLB(s) of those one or more non-ionic surfactants.

In certain embodiments, Applicants' pain relief pellet includes one ormore lubricants, including, for example, magnesium stearate and/orcroscarnellose sodium, especially as sold under the trademark Ac-Di-Sol®by FMC. Such lubricants are present in an amount up to about 5.0 weightpercent. Applicants' anesthetic composition may optionally also includea wide range of additives to facilitate application, to control release,to stabilize the composition and for other reasons well known in theart.

In certain embodiments, Applicants' method utilizes an implanter havinga pellet magazine in combination with an injection needle, as well asstructure permitting injection of pellets from the magazine through theneedle for implantation under the skin of an animal. In certainembodiments of Applicants' method, the magazine is loaded with painrelief pellets and pharmaceutical pellets for distribution in sequencesingly. In alternative embodiments, the magazine is loaded with painrelief pellets and pharmaceutical pellets for distribution in multiplesinto the same injection site.

Broadly speaking, the pellet system used in Applicants' method includesan implanter apparatus for subcutaneously implanting pharmaceuticalpellets in an animal through the bore of a hypodermic needle which isremotely coupled to a pellet magazine, and a plurality of pellets sizedto be implanted through the needle and positioned in the magazine forselective alignment of a pellet with the needle. In one embodiment, thepellets include one or more pharmaceutical doses, and at least one painrelief pellet. In certain embodiments, that pain relief pellet includesone or more anti-inflammatory agents. These various pellets are arrangedin the magazine in sequential order for simultaneous delivery of apharmaceutical dose and an anesthetic/analgesic/anti-inflammatory doseas part of a single injection.

Referring to FIG. 1, general the reference numeral 10 represents apellet implantation system in accordance with the invention. Theimplantation system 10 broadly includes a slide action implanterapparatus 12 which is used to implant solid form drugs orpharmaceuticals, such as pain relief pellets 40 (FIG. 2) andpharmaceutical pellets 42 (FIG. 2) from a magazine strip 16 into ananimal 30 through a hypodermic needle 18. The needle 18 is utilized byan operator 26 to create an opening 44 that produces an implantreceiving puncture 44 (FIG. 2) in the animal 30.

A suitable implanter apparatus 12 is illustrated and described in detailin U.S. Pat. No. 5,522,797, which is hereby incorporated herein, andgenerally includes a housing 20 having a grip 22 with a trigger assembly24 pivotally mounted therein. An impeller 17 is slidably mounted withinthe housing 20 in alignment with an interior bore 46 (FIG. 2) of theneedle 18 and aligned chambers 16 of the loaded pellet magazine strip14. The needle 18 is used to puncture through the skin or hide 32 of ananimal's ear 34, and the trigger 24 is squeezed toward the grip 22 ofthe housing 20 to initiate injection of the pellets 40 and 42 and so asto cause the impeller 17 to be urged through the magazine chamber 16 andneedle bore 46, thereby forcing the pellets 40 and 42 through the bore46 of needle 18 and into the puncture 44 in the ear 34.

Each magazine strip 14 of the implanter 12 typically contains multipleparallel aligned pellet doses stored in corresponding pellet chambers16, which are connected by interconnecting webs 28. The chambers 16 areslightly conical in shape and are arranged in a side-by-side parallelrelation. The chambers 16 may have internal frictional formations suchas beads or posts (not shown) to retain the pellets 40 and 42 thereinprior to insertion and which can be easily bypassed by application ofpressure to the trigger 24. A plurality of strips 14 can be connected inend-to-end relation to increase the implanting capacity before theimplanter 12 requires reloading. As the pellets 40 and 42 in anindividual magazine strip 14 are exhausted the empty strip 14 can bedetached from the remaining strips 14 located in the implanter 12 anddiscarded.

Each pellet chamber 16 is loaded with an arrangement of pellets 40 and42. The pellets 40 and 42 are composed of one or more activeingredients, either alone, formed into a pellet, in conjunction with oneor more excipients, formed as part of a polymeric based release systemsuch as co-extruded polymers or matrix polymer systems, or included aspart of a delivery system based on mass transfer through an opening or agel matrix, either by diffusion or osmotic pressure pumping of theactive ingredient.

Pellets 42 are formulated to include pharmaceuticals such asantibiotics, insulin, endocrine hormones (such as growth and birthcontrol hormones), vaccines, parasiticides or other biocides. Thus incertain embodiments, one pellet 40 contains an anesthetic/analgesiccomposition/anti-inflammatory composition, and the other pellet 42contains one or more pharmaceutical agents. It is foreseen that thenumber of pellets for each group may vary or that the pain reliefagent(s) and other non-pain relief pharmaceuticals may be mixed in oneor more of the pellets 40.

Each magazine chamber 16 is prefilled with a preferred number ofdiscrete pellets 42, each containing a dose of one or morepharmaceuticals such as trenbolone acetate bovine growth hormone, alongwith at least one pellet 40 containing ananesthetic/analgesic/anti-inflammatory composition. The magazine strip14 is preferably loaded onto implanter housing 20 in an orientation sothat the pharmaceutical pellet 42 will be delivered first, followed bythe anesthetic pellet 40.

In use, an operator grasps the implanter 12 by the grip 22 and urges theneedle 18 into the hide 32 and under the skin of the target animal 30 tomake the implant-receiving puncture 44. The puncture 44 shown in FIG. 2is incomplete and the depth of the implant receiving puncture 44 shownin FIG. 2 is about half of the total depth as shown in FIG. 3. Theoperator 26 depresses the trigger member 24, thereby propelling a pin 50(FIG. 3) of the impeller member 17 forwardly through an aligned magazinechamber 16, forcing the pellets 40 and 42 through the needle bore 46 andinto the implant receiving puncture 44. The operator 26 then withdrawsthe needle 18, leaving the pellets 40 and 42 in the implant-receivingpuncture 44.

While the pharmaceuticals in pellet 42 are absorbed and utilizedsystemically by the animal 30, in one embodiment pellet 40 preferablydelivers most of its dose at the site of the implant receiving puncture44, although some of the anesthetic/analgesic/anti-inflammatory agent(s)may be absorbed and carried systemically. In this embodiment, pellet 40is preferably specifically formulated to deliver its dose locally ratherthan systemically, and at a controlled, predetermined rate over apreselected period of time. In another embodiment, pellet 40 isformulated to deliver a systemic anesthetic/analgesic/anti-inflammatorydose.

Those skilled in the art will appreciate that the magazine strip 14 maybe loaded for selective injection of more than one pain relief pellet40. Where a number of pellets 42 of pharmaceutical are to be delivered,the pharmaceutical may be sandwiched between two or more pain reliefpellets to provide localized anesthetic release at both ends of a longimplant receiving puncture 44. It is foreseen that in other embodimentspain relief pellets may be alternated in a stack of pellets of otherpharmaceuticals, for delivery throughout the implant-receiving puncture44.

Applicants' implantable pain relief pellets, and method to relieve painusing same, may be employed efficaciously with cows, horses, sheep,swine, dogs, cats or any other suitable animal, including humans.

While the invention has been described in detail herein in accordancewith certain preferred embodiments thereof, many modifications andchanges therein my be effected by those skilled in the art. Accordingly,it is intended by the appended claims to cover all such modificationsand changes as fall within the true spirit and scope of the invention.

1. An implantable pellet, comprising 95 weight percent of one or morepain relief agents, and 5 weight percent poly-2-ethyl-2-oxazoline havinga formula:

wherein n is 5000.